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Antiviral%20chemotherapy

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Title: Antiviral%20chemotherapy


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The head of a pin can hold five hundred million
rhinoviruses (cause of the common cold).One
sneeze can generate an aerosol of enough cold
viruses to infect thousands of people!
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Antiviral chemotherapy
  • Virus Structure and Replication
  • Viruses are the smallest infective agent,
    effectively consisting of nucleic acid (DNA
    or RNA) enclosed in a protein coat.
  • Viruses are intracellular parasites with
    no, or little, metabolic machinery of their
    own.
  • They have to borrow the biochemistry of
    the host cell to succeed and grow (this is
    what makes selective antiviral therapy so
    difficult).

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Antiviral chemotherapy
  • The virus attaches to specific receptors on
    the host cell surface which are normal
    membrane components. Usually ion channels,
    neurotransmitter receptors.
  • The receptor/virus complex enters the cell
    by receptor-mediated endocytosis during which
    the virus coat may be removed.
  • The nucleic acid of the virus then hijacks
    the cellular machinery for replicating
    viral nucleic acids and proteins for the
    manufacture of new virus particles.

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Antiviral chemotherapy
  • The genome of DNA viruses enters the cell
    nucleus and uses host RNA polymerase to
    produce virus-specific proteins.
  • After assembly of coat proteins around the
    viral DNA, complete virions are released by
    budding or after cell lyses.
  • Generally, RNA virus replication occurs
    solely in the cytoplasm and doesnt involve
    the cellular nucleus. (influenza are an
    exception since they have a requirement for
    active cellular transcription).

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Treatment of Herpesviruses Varicella-zoster,Cyto
megalavirus,Herpes simplex
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Anti-metabolites
  • False DNA building blocks or nucleosides. A
    nucleoside consists of a nucleobase and the sugar
    deoxyribose.
  • In antimetabolites, one of the components is
    defective. In the body, the abnormal nucleosides
    undergo bioactivation by attachment of three
    phosphate residues
  • Acyclovir has both specificity of the highest
    degree and optimal tolerability, because it
    undergoes bioactivation only in infected cells,
    where it preferentially inhibits viral DNA
    synthesis.

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Acyclovir
  • A virally coded thymidine kinase (specific to
    H.simplex and varicella-zoster virus) performs
    the initial phosphorylation step the remaining
    two phosphate residues are attached by cellular
    kinases.
  • Acyclovir triphosphate inhibits viral DNA
    polymerase resulting in chain termination.
  • It is 30-fold more potent against the virus
    enzyme than the host enzyme.
  • Acyclovir is active against herpes simplex
    and varicellar-zoster virus.
  • It is rapidly broken down in cells, is
    orally active and is relatively non-toxic
    systemically.

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Acyclovir and Valacyclovir (pro-drug, better
availability)
  • A Guanine analogue with antiviral for Herpes
    group only

Acyclovir
AcycloGMP
AcycloGTP
Thymidine kinase
Cellular kinases
Viral 200x affinity of mammalian
  1. Inhibits viral DNA polymerase selectively
  2. Incorporated into DNA and terminates synthesis

Resistance 1. ? activity of thymidine kinase 2.
altered DNA polymerase
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Acyclovir
  • Acyclovir is used to treat
  • Herpes simplex infections (genital herpes,
    and herpes encephalitis).
  • Chickenpox in immuno-compromised patients.
  • Prophylactically in patients treated with
    immunosuppressant drugs or radiotherapy who
    are in danger of infection by reactivation
    of latent virus.
  • Prophylactically in patients with frequent
    recurrences of genital herpes.

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  • Oral acyclovir has multiple uses. In first
    episodes of genital herpes, oral acyclovir
    shortens the duration of symptoms by
    approximately 2 days, the time to lesion healing
    by 4 days, and the duration of viral shedding by
    7 days. In recurrent genital herpes, the time
    course is shortened by 12 days.
  • Oral acyclovir is only modestly beneficial in
    recurrent herpes labialis.
  • Topical acyclovir cream is substantially less
    effective than oral therapy for primary HSV
    infection. It is of no benefit in treating
    recurrent genital herpes.

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Acyclovir
  • Common adverse drug reactions are nausea,
    vomiting, diarrhea and headache.
  • Additional common adverse effects, when acyclovir
    is administered IV, include
  • Renal insufficiency and neurologic toxicity
  • However, incommon with adequate hydration and
  • avoidance of rapid infusion rate.

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Docosanol
  • Docosanol is a saturated 22-carbon aliphatic
    alcohol that inhibits fusion between the plasma
    membrane and the HSV envelope, thereby preventing
    viral entry into cells and subsequent viral
    replication.
  • Topical docosanol 10 cream is available without
    a prescription application site reactions occur
    in approximately 2 of patients.
  • When applied within 12 hours of the onset of
    prodromal symptoms, five times daily, median
    healing time was shortened by 18 hours compared
    with placebo in recurrent orolabial herpes.

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Ganciclovir
  • Mechanism like Acyclovir
  • Active against all Herpes viruses including CMV
    (100 time than acyclovir)
  • Low oral bioavailability given I.V.
  • Most common adverse effect bone marrow
    suppression (leukopenia 40, thrombocytopenia
    20) and CNS effects (headache, behavioral,
    psychosis, coma, convulsions).
  • 1/3 of patients have to stop because of adverse
    effects
  • Drug of choice for CMV infections retinitis,
    pneumonia, colitis.

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Foscarnet
  • An inorganic pyrophosphate analog
  • Active against Herpes (I, II, Varicella , CMV),
    including those resistant to Acyclovir and
    Ganciclovir.
  • Direct inhibition of DNA polymerase and Reverse
    Transcriptase
  • Nephrotoxicity (25) most common side effect
  • Use (1) CMV retinitis and other CMV infections
    instead of ganciclovir
  • (2) H. simplex resistant to Acyclovir.
  • (3) HIV.

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Vidarabine
  • Inhibits virally induced DNA polymerase more
    strongly than it does the endogenous enzyme.
  • Vidarabine is a chain terminator and is
    active against herpes simplex, varicella
    zoster, and vaccinia are especially
    sensitive.
  • Its use is now limited to topical treatment of
    severe herpes simplex infection. Before the
    introduction of the better tolerated acyclovir,
    vidarabine played a major part in the treatment
    of herpes simplex encephalitis.
  • Its clinically used in treatment of
    immunocompromised patients with herpetic and
    vaccinia keratitis and in keratoconjunctivitis.

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  • Treatment of respiratory virus infection
  • Influenza A B
  • Respiratory suncytial virus (RSV)

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Attachment Inhibitors
  • The primary antiviral mechanism of Amantadine and
    Rimantadine is to block the viral membrane
    matrix protein, which function as an ion channel
    that is required for the fusion of the viral
    membrane with the cell membrane.
  • Their clinical use is limited to Influenza A
    infection.
  • They are very effective in preventing infection
    if the treatment is begun at the time of-or prior
    to- exposure to the virus.

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Attachment Inhibitors
  • Side effects of Amantadine are mainly associated
    with the CNS, such as ataxia and dizziness.
  • While Rimantadine produce little CNS effect
    because it does not penetrate the blood brain
    barrier.
  • Both should be used with caution in pregnant and
    nursing women.

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Neuroaminidase inhibitors
  • Oseltamivir and Zanamavir
  • Mechanism of action
  • Viral neuraminidase catalyzes cleavage of
    terminal sialic acid residues attached to
    glycoproteins and glycolipids, a process
    necessary for release of virus from host cell
    surfaces.
  • Neuraminidase inhibitors thus prevent release of
    virions from infected cell

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Neuroaminidase inhibitors
  • Administration of neuraminidase inhibitors is a
    treatment that limits the severity and spread of
    viral infections.
  • Neuraminidase inhibitors are useful for combating
    influenza infection
  • zanamivir, administered by inhalation
  • oseltamivir, administered orally.
  • Toxicities
  • Exacerbation of reactive airway disease by
    zanamavir
  • Nausea and vomiting for oseltamivir

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oseltamivir
  • Early administration is crucial because
    replication of influenza virus peaks at 2472
    hours after the onset of illness.
  • When a 5-day course of therapy is initiated
    within 3648 hours after the onset of symptoms,
    the duration of illness is decreased by 12 days
    compared with those on placebo,
  • severity is diminished, and the incidence of
    secondary complications in children and adults
    decreases.
  • Once-daily prophylaxis is 7090 effective in
    preventing disease after exposure.

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Ribavirin
  • It is an antimetabolite that inhibits influenza
    RNA polymerase non-competitively in vitro but
    poorly in vivo.
  • An aerosol form is used against RSV (respiratory
    syncytial virus) and the drug is used
    intravenously against Lassa fever.
  • Adverse reactions includes Anemia due to
    hemolysis and bone marrow suppression

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Antiretroviral agents
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HIV Life Cycle
Step 1 Fusion
Step 3 Integration
reverse transcriptase
HIV
Step 5 Packaging and Budding
Step 2 Transcription
Step 4 Cleavage
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Azidothymidine (Zidovudin(AZT))
  • It is a potent antagonist of reverse
    transcriptase, It is a chain terminator.
  • Cellular enzyme phosphorylate AZT to the
    triphosphate form which inhibits RT and causes
    chain termination
  • It is widely use in the treatment of AIDS
    (The only clinical use).
  • AZT is toxic to bone marrow, for example, it
    cause severe anaemia and leukopenia In patient
    receiving high dose. Headache is also common

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Didanosine (Dideoxyinosine)
  • Didanosine act as chain terminators and
    inhibitors of reverse transcriptase because
    they lack a hydroxyl group.
  • is phosphorylated to the active metabolite of
    dideoxyadenosine triphosphate
  • It is used in the treatment of AIDS (second
    drug approved to treat HIV-1 infection).
  • They are given orally,
  • and their main toxicities are pancreatitis,
    peripheral neuropathy, GI disturbance, bone
    marrow depression.

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Non-nucleoside Non-competitive RT inhibitors
(1) bind to viral RT, inducing conformational
changes that result in enzyme inhibition (2)
Combination therapy with AZT (resistant mutants
rapidly emerge, little use in monotherapy) (3)
Resistance mutations will be at different
sites
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Non-nucleoside Non-competitive RT inhibitors
  • Nevirapine Approved for AIDS patients, Good
    blocker of mother to child transmission
    (perinatal - breast feeding)
  • Single dose at delivery reduced HIV transmission
    by 50
  • Single dose to baby by 72 hours

NNRTIs Adverse Effects RASH!! CNS effects
(e.g. sedation, insomnia, vivid dreams,
dizziness, confusion, feeling of disengagement)
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Rash
Rash, occurs in up to 20 of patients, usually in
the first 46 weeks of therapy. Although
typically mild and self-limited, rash is
dose-limiting in about 7 of patients. Women
appear to have an increased incidence of rash.
When initiating therapy, gradual dose
escalation over 14 days is recommended to
decrease the incidence of rash.
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Protease Inhibitors
  • HIV Protease Inhibitors have significantly
    alter the course of the HIV disease.
  • All are reversible inhibitors of HIV Protease-the
    viral enzyme responsible for cleavage of viral
    polyprotein into number of essential enzymes
    (reverse transcription, polymerase).
  • Examples are Saquinavir, and Ritonavir.
  • They are orally active, side effects include
    GI disturbances and hyperglycemia, interact
    with cytochrome P450. buffalo hump

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Anti-Viral Chemotherapy
GAG/POL polyprotein
GAG
Integrase
Polymerase
Protease
Retrovirus --- HIV
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Anti-Viral Chemotherapy
GAG
Integrase
Polymerase
Protease folds and cuts itself free
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Anti-Viral Chemotherapy
GAG
Integrase
Polymerase
Protease cuts at a site between the integrase and
polymerase
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Anti-Viral Chemotherapy
GAG
Integrase
polymerase
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New targets
  • Enfuvirtide is Peptides derived from gp41 can
    inhibit infection, probably by blocking the
    interaction of gp41 with cell membrane proteins
    during fusion.
  • Raltegravir (Integrase Inhibitor) targets
    integrase, an HIV enzyme that integrates the
    viral genetic material into human chromosomes, a
    critical step in the pathogenesis of HIV.
  • Maraviroc It blocks the interaction between
    chemokine receptor CCR5 and HIV gp120.

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(HAART)
  • Highly active anti-retroviral therapies
  • Combination therapies (triple drug cocktail,
    HAART) are very effective and can reduce viral
    load in the patient below detectable levels
    implying that HIV replication has ceased.
  • examples (1) NNRTIBased Regimens (1-NNRTI
    2NRTIs)
  • (2) PI-Based Regimens (1 or 2 PIs 2
    NRTIs)
  • The trouble with all of these complicated drug
    regimens is compliance. The components  of HAART
    must be taken at different times.
  • Non-compliance with protease inhibitor therapy is
    of serious concern as the new virus that emerges
    is resistant to the inhibitor being taken and
    also resistant to other protease inhibitors.

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Anti-Hepatitis B Virus Agents
Figure 2. Timeline of evolution of HBV therapies,
United States.
45
Interferons 
  • Interferon Alfa
  • Endogenous proteins induce host cell enzymes
    that inhibit viral RNA translation and cause
    degradation of viral mRNA and tRNA .
  • Bind to membrane receptors on cell surface , May
    also inhibit viral penetration, uncoating, mRNA
    synthesis, and translation, and virion assembly
    and release.
  • Pegylated interferon Alfa
  • A linear or branced polyethylene gylcol (PEG)
    moiety is attached covalently to interferon
  • Increased half-life and steady drug
    concentrations  

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Interferons 
  • a limited treatment course (ie, only 1 year of
    therapy),
  • lack of resistance development.
  • Disadvantages include a high rate of
    treatment-related adverse events. flu-like
    symptoms increased body temperature, feeling
    ill, fatigue, headache, muscle pain.

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Anti-Hepatitis C Virus Agents
  • Approved
  • Interferon-alpha (pegylated)
  • Ribavirin
  • In development
  • Protease inhibitors
  • Polymerase inhibitors

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  • In pregnancy , a regimen of oral zidovudine
    beginning between 14 and 34 weeks of gestation,
    intravenous zidovudine during labor, and
    zidovudine syrup to the neonate from birth
    through 6 weeks of age has been shown to reduce
    the rate of vertical (mother-to-newborn)
    transmission of HIV by up to 23.
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